ABSTRACT The goal of this K08 grant is to allow Dr. Daniel Chao, M.D., Ph.D. to obtain the necessary scientific training and professional skills to become an independent investigator in the field of age-related macular degeneration (AMD). A pathologic hallmark of nonexudative AMD is the presence of drusen, lipid deposits below the retinal pigment epithelium (RPE), which leads to RPE atrophy and photoreceptor death. Mechanisms underlying drusen biogenesis and RPE atrophy are poorly understood, and currently there is no therapy which slows the progression of nonexudative AMD. Long chain polyunsaturated acids (LC- PUFAs) have been implicated in AMD pathogenesis through biochemical and epidemiology studies; however the molecular mechanisms by which PUFAs contribute to AMD is poorly understood. Our preliminary data suggests that ELOVL2, a key enzyme in elongation of LC-PUFAs, plays a key role in drusen biogenesis. Our central hypothesis is that ELOVL2 activity in the retinal pigment epithelium prevents drusen-like deposit formation, and that omega-3 products of ELOVL2 elongation are responsible for this effect. We will test this hypothesis through the following specific aims: 1) Characterization of metabolic and molecular changes in RPE lacking ELOVL2 enzymatic activity 2) Determine the extent that ELOVL2 expression in the RPE is required for drusen-like deposit formation through cell specific rescue experiments in vivo, and 3) Dissect the roles of omega-3 and omega-6 products of ELOVL2 elongation through lipid supplementation in ELOVL2 mutant animals. Our proposed studies are significant because they characterize a novel gene and pathway in drusen formation. The positive translational impact is the potential development of novel therapeutic strategies for treatment of nonexudative AMD. To achieve this, Dr. Chao has assembled an exceptional mentoring team at UCSD consisting of Dr. Jonathan Lin, M.D., Ph.D. an expert in retinal degenerative diseases, and Dr. Dorota Skowronska-Krawczyk, PhD, an expert on molecular mechanisms of aging in eye diseases. This is complemented by an external clinician-scientist committee with experience in macular degeneration research and clinician-scientist career development. Key components of this training plan include 1) acquisition of scientific and technical expertise to use the mouse model to study drusen biogenesis 2) formal didactic courses in grant writing, mouse genetics, and lipid biology 3) generation of preliminary data for an R01 submission, and 4) planned transition to independence through mentorship. This work takes place within the outstanding scientific environment and world class facilities at UCSD and the department of ophthalmology, which has a strong track record of producing successful clinician-scientists. Combined with his training in clinical training in vitreoretinal surgery, this training plan will allow Dr. Chao to become a leading clinician-scientist with an independent R01- funded research program focused on identifying new therapies for macular degeneration.